Combination pharmacological therapy targeting multiple mechanisms of sleep apnoea: a randomised controlled cross-over trial.

RATIONALE: Acetazolamide and atomoxetine-plus-oxybutynin ('AtoOxy') can improve obstructive sleep apnoea (OSA) by stabilising ventilatory control and improving dilator muscle responsiveness respectively. Given the different pathophysiological mechanisms targeted by each intervention, we tested whether AtoOxy-plus-acetazolamide would be more efficacious than AtoOxy alone. METHODS: In a multicentre randomised crossover trial, 19 patients with moderate-to-severe OSA received AtoOxy (80/5 mg), acetazolamide (500 mg), combined AtoOxy-plus-acetazolamide or placebo at bedtime for three nights (half doses on first night) with a 4-day washout between conditions. Outcomes were assessed at baseline and night 3 of each treatment period. Mixed model analysis compared the reduction in Apnoea-Hypopnoea Index (AHI) from baseline between AtoOxy-plus-acetazolamide and AtoOxy (primary outcome). Secondary outcomes included hypoxic burden and arousal index. RESULTS: Although AtoOxy lowered AHI by 49 (33, 62)%baseline (estimate (95% CI)) vs placebo, and acetazolamide lowered AHI by+34 (14, 50)%baseline vs placebo, AtoOxy-plus-acetazolamide was not superior to AtoOxy alone (difference: -2 (-18, 11)%baseline, primary outcome p=0.8). Likewise, the hypoxic burden was lowered with AtoOxy (+58 (37, 71)%baseline) and acetazolamide (+37 (5, 58)%baseline), but no added benefit versus AtoOxy occurred when combined (difference: -13 (-5, 39)%baseline). Arousal index was also modestly reduced with each intervention (11%baseline-16%baseline). Mechanistic analyses revealed that similar traits (ie, higher baseline compensation, lower loop gain) were associated with both AtoOxy and acetazolamide efficacy. CONCLUSIONS: While AtoOxy halved AHI, and acetazolamide lowered AHI by a third, the combination of these leading experimental interventions provided no greater efficacy than AtoOxy alone. Failure of acetazolamide to further increase efficacy suggests overlapping physiological mechanisms. TRIAL REGISTRATION NUMBER: NCT03892772.

Polysomnographic airflow shapes and site of collapse during drug-induced sleep endoscopy.

BACKGROUND: Differences in the pharyngeal site of collapse influence efficacy of non-continuous positive airway pressure therapies for obstructive sleep apnoea (OSA). Notably, complete concentric collapse at the level of the palate (CCCp) during drug-induced sleep endoscopy (DISE) is associated with reduced efficacy of hypoglossal nerve stimulation, but CCCp is currently not recognisable using polysomnography. Here we develop a means to estimate DISE-based site of collapse using overnight polysomnography. METHODS: 182 OSA patients provided DISE and polysomnography data. Six polysomnographic flow shape characteristics (mean during hypopnoeas) were identified as candidate predictors of CCCp (primary outcome variable, n=44/182), including inspiratory skewness and inspiratory scoopiness. Multivariable logistic regression combined the six characteristics to predict clear presence (n=22) versus absence (n=128) of CCCp (partial collapse and concurrent tongue base collapse excluded). Odds ratios for actual CCCp between predicted subgroups were quantified after cross-validation. Secondary analyses examined complete lateral wall, tongue base or epiglottis collapse. External validation was performed on a separate dataset (ntotal=466). RESULTS: CCCp was characterised by greater scoopiness (ß=1.5±0.6 per 2sd, multivariable estimate±se) and skewness (ß=11.4±2.4) compared with non-CCCp. The odds ratio for CCCp in predicted positive versus negative subgroups was 5.0 (95% CI 1.9-13.1). The same characteristics provided significant cross-validated prediction of lateral wall (OR 6.3, 95% CI 2.4-16.5), tongue base (OR 3.2, 95% CI 1.4-7.3) and epiglottis (OR 4.4, 95% CI 1.5-12.4) collapse. CCCp and lateral wall collapse shared similar characteristics (skewed, scoopy), diametrically opposed to tongue base and epiglottis collapse characteristics. External validation confirmed model prediction. CONCLUSIONS: The current study provides a means to recognise patients with likely CCCp or other DISE-based site of collapse categories using routine polysomnography. Since site of collapse influences therapeutic responses, polysomnographic airflow shape analysis could facilitate precision site-specific OSA interventions.

Adverse pregnancy outcomes and pharyngeal flow limitation during sleep: Nulliparous Pregnancy Outcomes Study Monitoring Mothers-to-be (nuMoM2b).

BACKGROUND: Pharyngeal flow limitation during pregnancy may be a risk factor for adverse pregnancy outcomes but was previously challenging to quantify. Our objective was to determine whether a novel objective measure of flow limitation identifies an increased risk of pre-eclampsia (primary outcome) and other adverse outcomes in a prospective cohort: Nulliparous Pregnancy Outcomes Study Monitoring Mothers-to-be (nuMoM2b). METHODS: Flow limitation severity scores (0%=fully obstructed, 100%=open airway), quantified from breath-by-breath airflow shape, were obtained from home sleep tests during early (6-15 weeks) and mid (22-31 weeks) pregnancy. Multivariable logistic regression quantified associations between flow limitation (median overnight severity, both time-points averaged) and pre-eclampsia, adjusting for maternal age, body mass index (BMI), race, ethnicity, chronic hypertension and flow limitation during wakefulness. Secondary outcomes were hypertensive disorders of pregnancy (HDP), gestational diabetes mellitus (GDM) and infant birthweight. RESULTS: Of 1939 participants with flow limitation data at both time-points (mean±sd age 27.0±5.4 years and BMI 27.7±6.1 kg·m-2), 5.8% developed pre-eclampsia, 12.7% developed HDP and 4.5% developed GDM. Greater flow limitation was associated with increased pre-eclampsia risk: adjusted OR 2.49 (95% CI 1.69-3.69) per 2sd increase in severity. Findings persisted in women without sleep apnoea (apnoea-hypopnoea index <5 events·h-1). Flow limitation was associated with HDP (OR 1.77 (95% CI 1.33-2.38)) and reduced infant birthweight (83.7 (95% CI 31.8-135.6) g), but not GDM. CONCLUSIONS: Greater flow limitation is associated with increased risk of pre-eclampsia, HDP and lower infant birthweight. Flow limitation may provide an early target for mitigating the consequences of sleep disordered breathing during pregnancy.

Sleep Apnea Physiological Burdens and Cardiovascular Morbidity and Mortality.

Rationale: Obstructive sleep apnea is characterized by frequent reductions in ventilation, leading to oxygen desaturations and/or arousals. Objectives: In this study, association of hypoxic burden with incident cardiovascular disease (CVD) was examined and compared with that of "ventilatory burden" and "arousal burden." Finally, we assessed the extent to which the ventilatory burden, visceral obesity, and lung function explain variations in hypoxic burden. Methods: Hypoxic, ventilatory, and arousal burdens were measured from baseline polysomnograms in the Multi-Ethnic Study of Atherosclerosis (MESA) and the Osteoporotic Fractures in Men (MrOS) studies. Ventilatory burden was defined as event-specific area under ventilation signal (mean normalized, area under the mean), and arousal burden was defined as the normalized cumulative duration of all arousals. The adjusted hazard ratios for incident CVD and mortality were calculated. Exploratory analyses quantified contributions to hypoxic burden of ventilatory burden, baseline oxygen saturation as measured by pulse oximetry, visceral obesity, and spirometry parameters. Measurements and Main Results: Hypoxic and ventilatory burdens were significantly associated with incident CVD (adjusted hazard ratio [95% confidence interval] per 1 SD increase in hypoxic burden: MESA, 1.45 [1.14, 1.84]; MrOS, 1.13 [1.02, 1.26]; ventilatory burden: MESA, 1.38 [1.11, 1.72]; MrOS, 1.12 [1.01, 1.25]), whereas arousal burden was not. Similar associations with mortality were also observed. Finally, 78% of variation in hypoxic burden was explained by ventilatory burden, whereas other factors explained only <2% of variation. Conclusions: Hypoxic and ventilatory burden predicted CVD morbidity and mortality in two population-based studies. Hypoxic burden is minimally affected by measures of adiposity and captures the risk attributable to ventilatory burden of obstructive sleep apnea rather than a tendency to desaturate.

Sleep apnea patients with epiglottic collapse elevate their larynx more with swallowing; videofluoroscopic swallowing study of 80 patients.

OBJECTIVE: The epiglottis plays an integral role in the swallowing mechanism and is also implicated as an obstruction site in obstructive sleep apnea (OSA). The underlying causes of epiglottic collapse during sleep remain unclear. This study aimed to investigate the cognitive functions using the Loewenstein Occupational Therapy Cognitive Assessment (LOTCA) and the neurophysiological and anatomical factors using videofluoroscopic swallowing studies (VFSS). We compared patients with OSA exhibiting epiglottic collapse to those without, assessing differences in anatomical or neurophysiological characteristics. METHODS: The study included 12 patients with epiglottic collapse (Epi-group) and 68 without (non-Epi group), all undergoing overnight polysomnography (PSG), drug-induced sleep endoscopy (DISE), LOTCA, and VFSS. Oral transit time (OTT), pharyngeal delay time (PDT), and pharyngeal transit time (PTT) were considered as neurophysiological traits, and laryngeal elevation length (LE) as anatomical trait, and were measured across various test diets (10 ml of liquid, soft, or solid). RESULTS: The study comprised 80 individuals, 57 men and 23 women, with no significant age, sex, body mass index or PSG parameters between groups, or DISE findings, with the exception of epiglottic collapse. Swallowing metrics from VFSS were normal, with no differences in OTT, PDT, PTT, or LOTCA scores. Notably, patients with epiglottic collapse showed a greater laryngeal elevation when swallowing soft and solid foods (p = 0.025 and p = 0.048, respectively). CONCLUSIONS: Patients with epiglottic collapse do not exhibit neurophysiological or cognitive impairments when compared to non-Epi group. However, the Epi-group displayed a significantly increased laryngeal elevation length. This suggests that anatomical factors may have a more substantial role in the development of epiglottic collapse than neurophysiological factors.

Cardiovascular Benefit of Continuous Positive Airway Pressure in Adults with Coronary Artery Disease and Obstructive Sleep Apnea without Excessive Sleepiness.

Rationale: Randomized controlled trials of continuous positive airway pressure (CPAP) in patients with obstructive sleep apnea (OSA) have not demonstrated protection against adverse cardiovascular outcomes. Recently, observational studies revealed that OSA-related cardiovascular risk is concentrated in patients with an elevated pulse rate response to respiratory events (ΔHR). Objectives: Here, in this post hoc analysis of a prospective clinical trial, we test the hypothesis that a greater pretreatment ΔHR is associated with greater CPAP-related protection against adverse cardiovascular outcomes. Methods: ΔHR was measured from baseline polysomnography of the RICCADSA (Randomized Intervention with CPAP in CAD and OSA) randomized controlled trial (patients with coronary artery disease [CAD] and OSA [apnea-hypopnea index ⩾ 15 events/h] with Epworth Sleepiness Scale score < 10; nCPAP:ncontrol = 113:113; male, 85%; age, 66 ± 8 [mean ± SD] yr). The primary outcome was a composite of repeat revascularization, myocardial infarction, stroke, and cardiovascular mortality. Multivariable Cox regression assessed whether the effect of CPAP was moderated by ΔHR (treatment-by-ΔHR interaction). Measurements and Main Results: The CPAP-related reduction in risk increased progressively with increasing pretreatment ΔHR (interaction hazard ratio [95% confidence interval], 0.49 [0.27 to 0.90] per SD increase in ΔHR; P < 0.05). This means that in patients with a ΔHR of 1 SD above the mean (i.e., 10 beats/min), CPAP was estimated to reduce cardiovascular risk by 59% (6% to 82%) (P < 0.05), but no significant risk reduction was estimated in patients with a mean ΔHR (6 beats/min; CPAP risk reduction, 16% [-53% to 54%]; P = 0.6). Conclusions: The protective effect of CPAP in patients with CAD and OSA without excessive sleepiness was modified by the ΔHR. Specifically, patients with higher ΔHR exhibit greater cardiovascular benefit from CPAP therapy.

Ventilatory Drive Withdrawal Rather Than Reduced Genioglossus Compensation as a Mechanism of Obstructive Sleep Apnea in REM Sleep.

Rationale: REM sleep is associated with reduced ventilation and greater obstructive sleep apnea (OSA) severity than non-REM (nREM) sleep for reasons that have not been fully elucidated. Objectives: Here, we use direct physiological measurements to determine whether the pharyngeal compromise in REM sleep OSA is most consistent with 1) withdrawal of neural ventilatory drive or 2) deficits in pharyngeal pathophysiology per se (i.e., increased collapsibility and decreased muscle responsiveness). Methods: Sixty-three participants with OSA completed sleep studies with gold standard measurements of ventilatory "drive" (calibrated intraesophageal diaphragm EMG), ventilation (oronasal "ventilation"), and genioglossus EMG activity. Drive withdrawal was assessed by examining these measurements at nadir drive (first decile of drive within a stage). Pharyngeal physiology was assessed by examining collapsibility (lowered ventilation at eupneic drive) and responsiveness (ventilation-drive slope). Mixed-model analysis compared REM sleep with nREM sleep; sensitivity analysis examined phasic REM sleep. Measurements and Main Results: REM sleep (⩾10 min) was obtained in 25 patients. Compared with drive in nREM sleep, drive in REM sleep dipped to markedly lower nadir values (first decile, estimate [95% confidence interval], -21.8% [-31.2% to -12.4%] of eupnea; P < 0.0001), with an accompanying reduction in ventilation (-25.8% [-31.8% to -19.8%] of eupnea; P < 0.0001). However, there was no effect of REM sleep on collapsibility (ventilation at eupneic drive), baseline genioglossus EMG activity, or responsiveness. REM sleep was associated with increased OSA severity (+10.1 [1.8 to 19.8] events/h), but this association was not present after adjusting for nadir drive (+4.3 [-4.2 to 14.6] events/h). Drive withdrawal was exacerbated in phasic REM sleep. Conclusions: In patients with OSA, the pharyngeal compromise characteristic of REM sleep appears to be predominantly explained by ventilatory drive withdrawal rather than by preferential decrements in muscle activity or responsiveness. Preventing drive withdrawal may be the leading target for REM sleep OSA.

Neural ventilatory drive decline as a predominant mechanism of obstructive sleep apnoea events.

BACKGROUND: In the classic model of obstructive sleep apnoea (OSA), respiratory events occur with sleep-related dilator muscle hypotonia, precipitating increased neural ventilatory 'drive'. By contrast, a drive-dependent model has been proposed, whereby falling drive promotes dilator muscle hypotonia to precipitate respiratory events. Here we determine the extent to which the classic versus drive-dependent models of OSA are best supported by direct physiological measurements. METHODS: In 50 OSA patients (5-91 events/hour), we recorded ventilation ('flow', oronasal mask and pneumotach) and ventilatory drive (calibrated intraoesophageal diaphragm electromyography, EMG) overnight. Flow and drive during events were ensemble averaged; patients were classified as drive dependent if flow fell/rose simultaneously with drive. Overnight effects of lower drive on flow, genioglossus muscle activity (EMGgg) and event risk were quantified (mixed models). RESULTS: On average, ventilatory drive fell (rather than rose) during events (-20 (-42 to 3)%baseline, median (IQR)) and was strongly correlated with flow (R=0.78 (0.24 to 0.94)). Most patients (30/50, 60%) were classified as exhibiting drive-dependent event pathophysiology. Lower drive during sleep was associated with lower flow (-17 (-20 to -14)%/drive) and EMGgg (-3.5 (-3.8 to -3.3)%max/drive) and greater event risk (OR: 2.2 (1.8 to 2.5) per drive reduction of 100%eupnoea); associations were concentrated in patients with drive-dependent OSA (ie, flow: -37 (-40 to -34)%/drive, OR: 6.8 (5.3 to 8.7)). Oesophageal pressure-without tidal volume correction-falsely suggested rising drive during events (classic model). CONCLUSIONS: In contrast to the prevailing view, patients with OSA predominantly exhibit drive-dependent event pathophysiology, whereby flow is lowest at nadir drive, and lower drive raises event risk. Preventing ventilatory drive decline is therefore considered a target for OSA intervention.

The Sleep Apnea-Specific Pulse-Rate Response Predicts Cardiovascular Morbidity and Mortality.

Rationale: Randomized controlled trials have been unable to detect a cardiovascular benefit of continuous positive airway pressure in unselected patients with obstructive sleep apnea (OSA). We hypothesize that deleterious cardiovascular outcomes are concentrated in a subgroup of patients with a heightened pulse-rate response to apneas and hypopneas (ΔHR). Methods: We measured the ΔHR in the MESA (Multi-Ethnic Study of Atherosclerosis) (N = 1,395) and the SHHS (Sleep Heart Health Study) (N = 4,575). MESA data were used to determine the functional form of the association between the ΔHR and subclinical cardiovascular biomarkers, whereas primary analyses tested the association of the ΔHR with nonfatal or fatal cardiovascular disease (CVD) and all-cause mortality in longitudinal data from the SHHS. Measurements and Main Results: In the MESA, U-shaped relationships were observed between subclinical CVD biomarkers (coronary artery calcium, NT-proBNP [N-terminal prohormone BNP], and Framingham risk score) and the ΔHR; notably, a high ΔHR (upper quartile) was associated with elevated biomarker scores compared with a midrange ΔHR (25th-75th centiles). In the SHHS, individuals with a high ΔHR compared with a midrange ΔHR were at increased risk of nonfatal or fatal CVD and all-cause mortality (nonfatal adjusted hazard ratio [95% confidence interval (CI)], 1.60 [1.28-2.00]; fatal adjusted hazard ratio [95% CI], 1.68 [1.22-2.30]; all-cause adjusted hazard ratio [95% CI], 1.29 [1.07-1.55]). The risk associated with a high ΔHR was particularly high in those with a substantial hypoxic burden (nonfatal, 1.93 [1.36-2.73]; fatal, 3.50 [2.15-5.71]; all-cause, 1.84 [1.40-2.40]) and was exclusively observed in nonsleepy individuals. Conclusions: Individuals with OSA who demonstrate an elevated ΔHR are at increased risk of cardiovascular morbidity and mortality. This study identifies a prognostic biomarker for OSA that appears useful for risk stratification and patient selection for future clinical trials.

Impact of cold and flu medication on obstructive sleep apnoea and its underlying traits: A pilot randomized controlled trial.

BACKGROUND AND OBJECTIVE: Animal studies indicate that alpha-1 adrenergic receptor agonists and antimuscarinic agents improve genioglossus muscle activity during sleep and may be candidates for the pharmacological treatment of OSA. On the other hand, noradrenergic stimulants may be wake-promoting or cause insomnia symptoms if taken before bedtime, and the addition of a medication with sedative properties, such as an antihistaminic, may reduce these side effects. In this study, we aimed to determine the effects of the combination of an alpha-1 adrenergic agonist (pseudoephedrine) and an antihistaminic-antimuscarinic (diphenhydramine) on OSA severity (AHI), genioglossus responsiveness and other endotypic traits (Vpassive , muscle compensation, LG and arousal threshold). METHODS: Ten OSA patients performed a randomized, placebo-controlled, double-blind, crossover trial comparing one night of pseudoephedrine 120 mg plus diphenhydramine 50 mg (DAW1033D) to placebo administered prior to sleep. The AHI, genioglossus muscle responsiveness to negative oesophageal pressure and the endotypic traits were measured via PSG. RESULTS: The participants' median (interquartile range) age was 50 (46-53) years and body mass index (BMI) was 34.3 (30.6-39.2) kg/m2 . The drug combination had no effect on AHI (21.6 (9.1-49.8) on placebo vs 37.9 (5.1-55.4) events/h on DAW1033D, P > 0.5) or genioglossus responsiveness (6.0 (2.6-9.2) on placebo vs 4.0 (3.5-7.3) %/cm H2 O). Amongst the phenotypic traits, only Vpassive was improved by 29 (3-55) % eupnoea, P = 0.03 (mean (95% CI)). CONCLUSION: The combination of pseudoephedrine and diphenhydramine did not improve OSA severity or genioglossus responsiveness but induced a small improvement in upper airway collapsibility, possibly due to the decongestant effect of the medications. The results of this study do not support the use of these medications for OSA treatment.

The Evaluation of Vertical Pole Configuration and Location on Assisting the Sit-to-Stand Movement in Older Adults with Mobility Limitations.

Grab-bars and transfer poles are common sit-to-stand aids for mobility limited older adults. This study investigated differences in kinetics and kinematics to characterize the lower-limb strength and dynamic balance requirements across different pole configurations and positions in nine mobility limited older adults. Poles were varied by location (near and far) and configuration (single vertical pole, double vertical poles, vertical pole with a horizontal bar). Results indicated that the far pole condition resulted in increased trunk (p < 0.001) and hip flexion (p < 0.01 and < 0.0001 for contralateral and ipsilateral sides, respectively), and a reduced peak vertical force applied to the pole (p < 0.001). Peak extension moments at the hip and knee were unchanged, and, therefore, pole position had no effect on task demands. Placing the pole unilaterally introduced a small kinetic asymmetry, which significantly increased peak knee extension moments on the ipsilateral side (p < 0.05). Finally, dynamic balance was relatively unchanged across pole conditions. These findings offer novel insight into pole use and the effect of varying pole location and configuration in a sample of older adults with mobility impairment, and provide the basis for future work.

Combined effects of auditory and visual cues on the perception of vection.

Vection is the illusion of self-motion in the absence of real physical movement. The aim of the present study was to analyze how multisensory inputs (visual and auditory) contribute to the perception of vection. Participants were seated in a stationary position in front of a large, curved projection display and were exposed to a virtual scene that constantly rotated around the yaw-axis, simulating a 360° rotation. The virtual scene contained either only visual, only auditory, or a combination of visual and auditory cues. Additionally, simulated rotation speed (90°/s vs. 60°/s) and the number of sound sources (1 vs. 3) were varied for all three stimulus conditions. All participants were exposed to every condition in a randomized order. Data specific to vection latency, vection strength, the severity of motion sickness (MS), and postural steadiness were collected. Results revealed reduced vection onset latencies and increased vection strength when auditory cues were added to the visual stimuli, whereas MS and postural steadiness were not affected by the presence of auditory cues. Half of the participants reported experiencing auditorily induced vection, although the sensation was rather weak and less robust than visually induced vection. Results demonstrate that the combination of visual and auditory cues can enhance the sensation of vection.

Combination Tonsillectomy and Hypoglossal Nerve Stimulation for Sleep Apnea Patients With Oropharyngeal Lateral Wall Collapse.

OBJECTIVE: The efficacy of hypoglossal nerve stimulation (HGNS) therapy is limited by obstruction of the oropharyngeal lateral walls (OLWs). Our objective was to investigate the effect of palatine tonsillectomy on HGNS efficacy in obstructive sleep apnea (OSA) patients with OLW collapse. STUDY DESIGN: Case-control study of patients with moderate-to-severe OSA, complete-or-partial OLW collapse, and small tonsils (1 - 2+). Concomitant palatine tonsillectomy and HGNS (HGNS+T) were compared against a control group of patients who underwent HGNS alone. SETTING: Single academic institution. METHODS: Study outcomes were measures of HGNS efficacy defined as a %reduction in apnea-hypopnea index (AHI) (primary) and successful treatment response (50% AHI reduction to <15/h, logistic regression), respectively. Regression analyses quantified the additional effect of tonsillectomy (HGNS+T vs HGNS alone, independent variable) on HGNS efficacy. Analyses were adjusted for OLW collapse severity (complete vs partial), tonsil size, age, sex, body mass index, and baseline AHI. RESULTS: Nineteen patients underwent HGNS+T and had follow-up sleep testing for the current analysis. The control group (HGNS alone) consisted of 78 patients. Baseline demographics and OSA severity were similar between the groups, except HGNS+T group had increased prevalence of complete OLW collapse. Linear regression demonstrated that adding tonsillectomy resulted in an additional 22.9% [7.5, 35.2] reduction in AHI [95% confidence interval, CI] (P = .006), and 8.6 [1.7,43.4] (P = .010) greater odds [95% CI] of a successful treatment response with HGNS. CONCLUSION: Compared to historically poorer outcomes of HGNS in patients with OLW collapse, these early results suggest combining tonsillectomy with HGNS may represent a promising strategy to improve success rates.

Physiological Determinants of Snore Loudness.

Rationale: The physiological factors modulating the severity of snoring have not been adequately described. Airway collapse or obstruction is generally the leading determinant of snore sound generation; however, we suspect that ventilatory drive is of equal importance. Objective: To determine the relationship between airway obstruction and ventilatory drive on snore loudness. Methods: In 40 patients with suspected or diagnosed obstructive sleep apnea (1-98 events/hr), airflow was recorded via a pneumotachometer attached to an oronasal mask, ventilatory drive was recorded using calibrated intraesophageal diaphragm electromyography, and snore loudness was recorded using a calibrated microphone attached over the trachea. "Obstruction" was taken as the ratio of ventilation to ventilatory drive and termed flow:drive, i.e., actual ventilation as a percentage of intended ventilation. Lower values reflect increased flow resistance. Using 165,063 breaths, mixed model analysis (quadratic regression) quantified snore loudness as a function of obstruction, ventilatory drive, and the presence of extreme obstruction (i.e., apneic occlusion). Results: In the presence of obstruction (flow:drive = 50%, i.e., doubled resistance), snore loudness increased markedly with increased drive (+3.4 [95% confidence interval, 3.3-3.5] dB per standard deviation [SD] change in ventilatory drive). However, the effect of drive was profoundly attenuated without obstruction (at flow:drive = 100%: +0.23 [0.08-0.39] dB per SD change in drive). Similarly, snore loudness increased with increasing obstruction exclusively in the presence of increased drive (at drive = 200% of eupnea: +2.1 [2.0-2.2] dB per SD change in obstruction; at eupneic drive: +0.14 [-0.08 to 0.28] dB per SD change). Further, snore loudness decreased substantially with extreme obstruction, defined as flow:drive <20% (-9.9 [-3.3 to -6.6] dB vs. unobstructed eupneic breathing). Conclusions: This study highlights that ventilatory drive, and not simply pharyngeal obstruction, modulates snore loudness. This new framework for characterizing the severity of snoring helps better understand the physiology of snoring and is important for the development of technologies that use snore sounds to characterize sleep-disordered breathing.

Mouth Closure and Airflow in Patients With Obstructive Sleep Apnea: A Nonrandomized Clinical Trial.

Importance: Mouth breathing is associated with increased airway resistance, pharyngeal collapsibility, and obstructive sleep apnea (OSA) severity. The common belief is that closing the mouth can mitigate the negative effects of mouth breathing during sleep. However, mouth breathing may serve as an essential route to bypassing obstruction along the nasal route (eg, the velopharynx). Objective: To investigate the role of mouth breathing as an essential route in some patients with OSA and its association with upper airway anatomical factors. Design, Setting, and Participants: This nonrandomized clinical trial included participants diagnosed with OSA who underwent drug-induced sleep endoscopy. Patients were stratified into 3 quantiles based on oral-breathing level (quantile 1: oral airflow < 0.05 L/min; quantile 2: oral airflow 0.05-2.2 L/min; quantile 3: oral airflow > 2.2 L/min). Interventions: Closing the mouth during sleep during alternating breaths by applying pressure to the mentum until teeth are in occlusion. Main Outcomes and Measures: The primary outcome was total inspiratory flow defined as the change in airflow in the transition from mouth relaxed to mouth closed, analyzed overall and by 3 oral-breathing quantiles. The association of velopharyngeal obstruction on the change in total inspiratory airflow was also investigated. Results: Of 66 enrolled patients with OSA, 12 were excluded due to insufficient baseline airflow. The analytic cohort consisted of 54 patients (39 [72%] male; median [IQR] age, 55 [46-64] years; apnea-hypopnea index, 26.9 [17.6-39.9] events/h; and body mass index calculated as weight in kilograms divided by height in meters squared, 28.9 [27.1-31.6]). Mouth closure increased total inspiratory flow by 27.8 percentage points overall (ß, 1.0 [95% CI, 0.4-1.9] L/min). However, outcomes varied based on the degree of baseline oral breathing. No association was found for 10 patients with near-zero mouth breathing (0.9 [95% CI, -0.2 to 2.1] L/min). Airflow improved with mouth closure in 32 patients with moderate levels of mouth breathing (2.0 [95% CI, 1.3-2.7] L/min), whereas it worsened in patients with high levels of mouth breathing (-1.9 [95% CI, -3.1 to -0.6] L/min). Velopharyngeal obstruction was associated with increased mouth breathing (0.6 [95% CI, 0.1-3.0] L/min) and reduced airflow with mouth closure (-1.9 [95% CI, -3.1 to -0.7] L/min). Conclusion and Relevance: Although mouth closure increased inspiratory airflow in the overall cohort of this nonrandomized clinical trial, the outcomes were heterogeneous. In patients who breathe primarily through their mouth during sleep and have velopharyngeal obstruction, airflow worsens with mouth closure. Hence, personalized approaches to treating mouth breathing should be considered. Trial Registration: ClinicalTrials.gov Identifier: NCT06547658.

Treatment of Sleep Apnea and Reduction in Blood Pressure: The Role of Heart Rate Response and Hypoxic Burden.

BACKGROUND: Obstructive sleep apnea is associated with increased blood pressure (BP). Obstructive sleep apnea treatment reduces BP with substantial variability, not explained by the apnea-hypopnea index, partly due to inadequate characterization of obstructive sleep apnea's physiological consequences, such as oxygen desaturation, cardiac autonomic response, and suboptimal treatment efficacy. We sought to examine whether a high baseline heart rate response (ΔHR), a marker of high cardiovascular risk in obstructive sleep apnea, predicts a larger reduction in post-treatment systolic BP (SBP). Furthermore, we aimed to assess the extent to which a reduction in SBP is explained by a treatment-related reduction in hypoxic burden (HB). METHODS: ΔHR and HB were measured from pretreatment and posttreatment polygraphy, followed by a 24-hour BP assessment in 168 participants treated with continuous positive airway pressure or nocturnal supplemental oxygen from the HeartBEAT study (Heart Biomarker Evaluation in Apnea Treatment). Multiple linear regression models assessed whether high versus mid (reference) ΔHR predicted a larger reduction in SBP (primary outcome) and whether there was an association between treatment-related reductions in SBP and HB. RESULTS: A high versus mid ΔHR predicted improvement in SBP (adjusted estimate, 5.8 [95% CI, 1.0-10.5] mm Hg). Independently, a greater treatment-related reduction in HB was significantly associated with larger reductions in SBP (4.2 [95% CI, 0.9-7.5] mm Hg per 2 SD treatment-related reduction in HB). Participants with substantial versus minimal treatment-related reductions in HB had a 6.5 (95% CI, 2.5-10.4) mm Hg drop in SBP. CONCLUSIONS: A high ΔHR predicted a more favorable BP response to therapy. Furthermore, the magnitude of the reduction in BP was partly explained by a greater reduction in HB.

Hypoxic Burden Based on Automatically Identified Desaturations Is Associated with Adverse Health Outcomes.

Rationale: Recent studies have shown that sleep apnea-specific intermittent hypoxemia quantified by the hypoxic burden (HB) predicted cardiovascular disease (CVD)-related mortality in community-based and clinical cohorts. Calculation of HB is based on manual scoring of hypopneas and apneas, which is time-consuming and prone to interscorer variability. Objective: To validate a novel method to quantify the HB that is based on automatically scored desaturations. Methods: The sample included 5,655 middle-aged or older adults from the Sleep Heart Health Study (52.8% women; age, 63.2 ± 11.3 yr). The original HB method was based on a subject-specific search window obtained from an ensemble average of oxygen saturation signals (as measured by pulse oximetry) and synchronized with respect to the termination of scored respiratory events. In this study, however, the search window was obtained from ensemble average of oxygen saturation signals that synchronized with respect to the minimum of all automatically identified desaturations (⩾2% and other thresholds, including 3% and 4%, in sensitivity analyses). The time interval between the two maxima around the minimum saturation was defined as the search window. The oximetry-derived HB (HBOxi) was defined as the total area under all desaturation curves (restricted by the search window) divided by the total sleep time. Logistic and Cox regression models assessed the adjusted odds ratio (aOR)/hazard ratio of excessive daytime sleepiness (EDS), hypertension (HTN), and CVD mortality per 1-standard deviation increase in HBOxi after adjusting for several covariates and confounders. Results: The Spearman's rank correlation between HB (median [interquartile range], 34.4 [18.4-59.8] % min/h) and HBOxi (median [interquartile range], 34.5 [21.6-53.8] % min/h) was 0.81 (P < 0.001). Similar to HB, HBOxi was significantly associated with EDS (aOR [95% confidence interval (CI)], 1.17 [1.09-1.26] per standard deviation), HTN (aOR [95% CI], 1.13 [1.05-1.21]), and CVD mortality (adjusted hazard ratio [95% CI], 1.15 [1.01-1.30]) in fully adjusted models. Conclusions: The HBOxi was highly correlated with the HB based on manually scored apneas and hypopneas and was associated with EDS, HTN, and CVD mortality with similar effect sizes as previously reported. This method could be incorporated into wearable technology that accurately records oxygen saturation signals.

Drive versus Pressure Contributions to Genioglossus Activity in Obstructive Sleep Apnea.

Rationale: Loss of pharyngeal dilator muscle activity is a key determinant of respiratory events in obstructive sleep apnea (OSA). After the withdrawal of wakefulness stimuli to the genioglossus at sleep onset, mechanoreceptor negative pressure and chemoreceptor ventilatory drive feedback govern genioglossus activation during sleep, but the relative contributions of drive and pressure stimuli to genioglossus activity across progressive obstructive events remain unclear. We recently showed that drive typically falls during events, whereas negative pressures increase, providing a means to assess their individual contributions to the time course of genioglossus activity. Objectives: For the first time, we critically test whether the loss of drive could explain the loss of genioglossus activity observed within events in OSA. Methods: We examined the time course of genioglossus activity (EMGgg; intramuscular electromyography), ventilatory drive (intraesophageal diaphragm electromyography), and esophageal pressure during spontaneous respiratory events (using the ensemble-average method) in 42 patients with OSA (apnea-hypopnea index 5-91 events/h). Results: Multivariable regression demonstrated that the falling-then-rising time course of EMGgg may be well explained by falling-then-rising drive and rising negative pressure stimuli (model R = 0.91 [0.88-0.98] [95% confidence interval]). Overall, EMGgg was 2.9-fold (0.47-∞) more closely associated with drive than pressure stimuli (ratio of standardized coefficients, ßdrive:ßpressure; ∞ denotes absent pressure contribution). However, individual patient results were heterogeneous: approximately one-half (n = 22 of 42) exhibited drive-dominant responses (i.e., ßdrive:ßpressure > 2:1), and one-quarter (n = 11 of 42) exhibited pressure-dominant EMGgg responses (i.e., ßdrive:ßpressure < 1:2). Patients exhibiting more drive-dominant EMGgg responses experienced greater event-related EMGgg declines (12.9 [4.8-21.0] %baseline/standard deviation of ßdrive:ßpressure; P = 0.004, adjusted analysis). Conclusions: Loss of genioglossus activity precipitating events in patients with OSA is strongly associated with a contemporaneous loss of drive and is greatest in those whose activity tracks drive rather than pressure stimuli. These findings were upheld for events without prior arousal. Responding to falling drive rather than rising negative pressure during events may be deleterious; future therapeutic strategies whose aim is to sustain genioglossus activity by preferentially enhancing responses to rising pressure rather than falling drive are of interest.

Pathophysiology Underlying Demographic and Obesity Determinants of Sleep Apnea Severity.

Rationale: Sleep apnea is the manifestation of key endotypic traits, including greater pharyngeal collapsibility, reduced dilator muscle compensation, and elevated chemoreflex loop gain. Objectives: We investigated how endotypic traits vary with obesity, age, sex, and race/ethnicity to influence sleep apnea disease severity (apnea-hypopnea index [AHI]). Methods: Endotypic traits were estimated from polysomnography in a diverse community-based cohort study (Multi-Ethnic Study of Atherosclerosis, N = 1,971; age range, 54-93 yr). Regression models assessed associations between each exposure (continuous variables per 2 standard deviations [SDs]) and endotypic traits (per SD) or AHI (events/h), independent of other exposures. Generalizability was assessed in two independent cohorts. Results: Greater AHI was associated with obesity (+19 events/h per 11 kg/m2 [2 SD]), male sex (+13 events/h vs. female), older age (+7 events/h per 20 yr), and Chinese ancestry (+5 events/h vs. White, obesity adjusted). Obesity-related increase in AHI was best explained by elevated collapsibility (+0.40 SD) and greater loop gain (+0.38 SD; percentage mediated, 26% [95% confidence interval (CI), 20-32%]). Male-related increase in AHI was explained by elevated collapsibility (+0.86 SD) and reduced compensation (-0.40 SD; percentage mediated, 57% [95% CI, 50-66%]). Age-related AHI increase was explained by elevated collapsibility (+0.37 SD) and greater loop gain (+0.15 SD; percentage mediated, 48% [95% CI, 34-63%]). Increased AHI with Chinese ancestry was explained by collapsibility (+0.57 SD; percentage mediated, 87% [95% CI, 57-100]). Black race was associated with reduced collapsibility (-0.30 SD) and elevated loop gain (+0.29 SD). Similar patterns were observed in the other cohorts. Conclusions: Different subgroups exhibit different underlying pathophysiological pathways to sleep apnea, highlighting the variability in mechanisms that could be targeted for intervention.

Within-night repeatability and long-term consistency of sleep apnea endotypes: the Multi-Ethnic Study of Atherosclerosis and Osteoporotic Fractures in Men Study.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is characterized by multiple "endotypic traits," including pharyngeal collapsibility, muscle compensation, loop gain, and arousal threshold. Here, we examined (1) within-night repeatability, (2) long-term consistency, and (3) influences of body position and sleep state, of endotypic traits estimated from in-home polysomnography in mild-to-severe OSA (apnea-hypopnea index, AHI > 5 events/h). METHODS: Within-night repeatability was assessed using Multi-Ethnic Study of Atherosclerosis (MESA): Traits derived separately from "odd" and "even" 30-min periods were correlated and regression (error vs. N windows available) provided a recommended amount of data for acceptable repeatability (Rthreshold = 0.7). Long-term consistency was assessed using the Osteoporotic Fractures in Men Study (MrOS) at two time points 6.5 ± 0.7 years apart, before and after accounting for across-year body position and sleep state differences. Within-night dependence of traits on position and state (MESA plus MrOS data) was estimated using bootstrapping. RESULTS: Within-night repeatability for traits ranged from R = 0.62-0.79 and improved to R = 0.69-0.83 when recommended amounts of data were available (20-35 7-min windows, available in 94%-98% of participants); repeatability was similar for collapsibility, loop gain, and arousal threshold (R = 0.79-0.83), but lower for compensation (R = 0.69). Long-term consistency was modest (R = 0.30-0.61) and improved (R = 0.36-0.63) after accounting for position and state differences. Position/state analysis revealed reduced loop gain in REM and reduced collapsibility in N3. CONCLUSIONS: Endotypic traits can be obtained with acceptable repeatability. Long-term consistency was modest but improved after accounting for position and state changes. These data support the use of endotypic assessments in large-scale epidemiological studies. CLINICAL TRIAL INFORMATION: The data used in the manuscript are from observational cohort studies and are not a part of the clinical trial.